近日来自浙江大学生命科学学院细胞与发育生物学研究所的研究人员从硬骨鱼中首次鉴别出Toll-IL-1受体家族的一个新成员DIGIRR，并证实其在IL-1信号通路中发挥重要的负调控作用。这一研究成果于7月29日在线发表在著名的免疫学期刊《免疫学期刊》（The Journal of Immunology）上。
Toll蛋白样受体（TLR）是在研究果蝇胚胎腹背侧体轴形成过程中新发现的一种介导机体天然免疫(innate immunity)的受体蛋白。因其结构、功能及信号转导途径均与白介素-1受体（IL-1R）类似，故统归于Toll/IL-1R家族。哺乳动物Toll受体称为Toll样受体（Toll like receptors, TLRs）。迄今为止，10种人类TLRs(human TLRs,hTLRs)已被先后发现。近年来大量研究证实Toll/IL-1R家族成员在炎症、免疫、病源体识别中都起着十分重要的作用，参与许多疾病的发病过程，与传染病、肿瘤、心血管病、自身免 疫性疾病、过敏等都有着密切关系。它亦是研究和开发新药的一个新的靶点，故受到国际医学生物学广泛关注。然而目前对科学家们其信号通路的负调控机制尚缺乏深入理解。
在这篇文章中，研究人员从三种硬骨鱼模型中首次鉴定出该家族的一个新成员，命名为Double-Ig-IL-1R Related Molecule (DIGIRR)，并证实这个DIGIRR分子包含有两个胞外Ig结构域，一个胞内Arg-Tyr536位点突TIR结构域，且定位于高尔基体的胞内受体。这些特征表明DIGIRR有别于其他已知的Toll/IL-1R家族成员。随后研究人员在体外实验中证实将DIGIRR注入到斑马鱼胚胎中可显著抑制脂多糖（LPS）和IL-1β诱导的NF-κB激活。当研究人员在斑马鱼体内用小干扰RNA(siRNA)沉默DIGIRR基因表达时发现在DIGIRR沉默的肝肾组织及白细胞中IL-1β即促炎细胞因子IL-6的表达水平显著增高。研究结果表明DIGIRR是LPS和IL-1β介导的信号传导通路及炎症反应中发挥重要的负调控因子作用。此外研究人员还证实一个胞外Ig结构域的缺失和胞内TIR结构域中Arg-Tyr536位点的突变，是IL-1R家族成员演化为负调节受体的重要机制。
浙江大学生命科学学院的邵建忠教授及项黎新副教授为这篇文章的共同通讯作者。这一研究获得了国家基础研究发展规划（973）项目（2006CB101805）、国家高技术研究发展计划（863）项目（2008AA09Z409）、国家自然科学基金（30871936, 31072234）以及浙江省科学技术基金（2007C12011）的资助。
Discovery of the DIGIRR Gene from Teleost Fish: A Novel Toll–IL-1 Receptor Family Member Serving as a Negative Regulator of IL-1 Signaling
Yi-feng Gu, Yu Fang, Yang Jin, Wei-ren Dong, Li-xin Xiang and Jian-zhong Shao
Toll–IL-1R (TIR) family members play crucial roles in a variety of defense, inflammatory, injury, and stress responses. Although they have been widely investigated in mammals, little is known about TIRs in ancient vertebrates. In this study, we report a novel double Ig IL-1R related molecule (DIGIRR) from three model fish (Tetraodon nigroviridis, Gasterosteus aculeatus, and Takifugu rubripes), adding a previously unknown homolog to the TIR family. This DIGIRR molecule contains two Ig-like domains in the extracellular region, one Arg-Tyr–mutated TIR domain in the intracellular region, and a unique subcellular distribution within the Golgi apparatus. These characteristics distinguish DIGIRR from other known family members. In vitro injection of DIGIRR into zebrafish embryos dramatically inhibited LPS-induced and IL-1β–induced NF-κB activation. Moreover, in vivo knockdown of DIGIRR by small interfering RNA significantly promoted the expression of IL-1β–stimulated proinflammatory cytokines (IL-6 and IL-1β) in DIGIRR-silenced liver and kidney tissues and in leukocytes. These results strongly suggest that DIGIRR is an important negative regulator of LPS-mediated and IL-1β–mediated signaling pathways and inflammatory responses. The Arg-Tyr–mutated site disrupted the signal transduction ability of DIGIRR TIR. Evolutionally, we propose a hypothesis that DIGIRR and single Ig IL-1R related molecule (SIGIRR) might originate from a common ancient IL-1R–like molecule that lost one (in DIGIRR) or two (in SIGIRR) extracellular Ig-like domains and intracellular Ser and Arg-Tyr amino acids. DIGIRR might be an evolutionary “transitional molecule” between IL-1R and SIGIRR, representing a shift from a potent receptor to a negative regulator. These results help define the evolutionary history of TIR family members and their associated signaling pathways and mechanisms.
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